Editors' ChoicePulmonary Hypertension

Stiff discipline for cells in pulmonary hypertension

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Science Translational Medicine  28 Sep 2016:
Vol. 8, Issue 358, pp. 358ec154
DOI: 10.1126/scitranslmed.aai8223

Pulmonary arterial hypertension (PAH) is a vascular disorder marked by elevated right ventricle blood pressure and arterial stiffness due to hyperproliferation of the pulmonary vascular endothelium and smooth muscle cells. Hyperproliferative cells support their increased growth by undergoing a metabolic shift toward glycolysis and diversion of tricarboxylic acid (TCA) cycle intermediates for biosynthesis. Spent TCA intermediates are replenished by a process known as anaplerosis, which is supported by up-regulation of key metabolic enzymes; for example, glutamine is deamidated by the enzyme glutaminase to generate glutamate, providing a point of entry into the TCA cycle.

Bertero et al. explored a fascinating link between vascular stiffness and hyperproliferation supported by glutaminase in pulmonary hypertension. Pulmonary endothelial and vascular smooth muscle cells cultured on stiff compared with soft matrices were both hyperproliferative and glycolytic. Knockdown of YAP and TAZ—transcriptional coactivators activated by cellular tension—inhibited these effects and also prevented the induction of the glutaminase GLS1. GLS1 inhibition or knockdown prevented stiffness-induced cellular hyperproliferation, which could be restored by addition of glutamate.

Pulmonary artery stiffness was increased in the rat monocrotaline model of pulmonary hypertension and glutamine measured in isolated pulmonary endothelial cells was decreased, suggestive of anaplerotic flux. GLS1 and YAP nuclear localization were increased in both smooth muscle and endothelium in the rat model, and small molecule inhibitors of collagen cross-linking, YAP, and GLS1 each reduced cellular proliferation and right ventricle blood pressures. Interestingly, YAP inhibition also decreased stiffness in a feed forward manner, suggesting a vicious cycle of stiffness, metabolic changes, and hyperproliferation with matrix remodeling.

Similar patterns of glutamine, GLS1, and YAP expression were also seen in rhesus macaques with simian immunodeficiency virus–associated pulmonary hypertension and in lung samples from human patients with PAH. Furthermore, blood samples collected from patients with pulmonary hypertension demonstrated higher blood lactate/pyruvate ratios than non-PAH patients, consistent with a shift to glycolytic metabolism, with lower blood glutamine/glutamate ratios noted in those patients who had higher pulmonary artery pressures.

The study by Bertero et al. sheds new light on how the vasculature imposes a “stiff discipline” on resident cells, instructing them to initiate a metabolic program resulting in the hyperproliferation and remodeling that are hallmarks of pulmonary hypertension. Moreover, the data provide a clear indication for therapies targeting matrix stiffness, YAP-TAZ signaling, and glutaminase function. The YAP inhibitor verteporfin, a drug that is FDA approved for macular degeneration, and CB-839, a GLS1 inhibitor already under early phase study for cancer, should now be tested in a therapeutic trial of patients with pulmonary hypertension.

T. Bertero et al., Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J. Clin. Invest. 126, 3313–3335 (2016). [Full Text]

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